A5047141760- Alzheimer's disease research and treatments
- Microtubule and mitosis dynamics
- Protein Structure and Dynamics
- Neuroscience and Neuropharmacology Research
- Prion Diseases and Protein Misfolding
- Photosynthetic Processes and Mechanisms
- Enzyme Structure and Function
- Cholinesterase and Neurodegenerative Diseases
- Cellular transport and secretion
- 14-3-3 protein interactions
- Computational Drug Discovery Methods
- Neuroinflammation and Neurodegeneration Mechanisms
- Supramolecular Self-Assembly in Materials
- Mitochondrial Function and Pathology
- Cellular Mechanics and Interactions
- Advanced Electron Microscopy Techniques and Applications
- Protist diversity and phylogeny
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Parkinson's Disease Mechanisms and Treatments
- Ubiquitin and proteasome pathways
- Advanced NMR Techniques and Applications
- Chemical Synthesis and Analysis
- Advanced Neuroimaging Techniques and Applications
- Cardiomyopathy and Myosin Studies
University Hospital Bonn
2023-2024
University of Bonn
2021-2024
German Center for Neurodegenerative Diseases
2014-2023
Center of Advanced European Studies and Research
2013-2022
University Hospital Cologne
2022
University of Cologne
2022
Robert Bosch (Germany)
2021
Max Planck Society
1986-2019
Max Planck Institute for Metabolism Research
2012-2019
Cytoskeleton (United States)
2000-2019
We have searched for a minimal interaction motif in τ protein that supports the aggregation into Alzheimer-like paired helical filaments. Digestion of repeat domain with different proteases yields GluC-induced fragment comprising 43 residues (termed PHF43), which represents third plus some flanking residues. This self assembles readily thin filaments without appearance, but these are highly competent to nucleate bona fide PHFs from full-length τ. Probing interactions PHF43 overlapping...
The transition between soluble intrinsically disordered tau protein and aggregated in neurofibrillary tangles Alzheimer's disease is unknown. Here, we propose that species can undergo liquid-liquid phase separation (LLPS) under cellular conditions phase-separated droplets serve as an intermediate toward aggregate formation. We demonstrate phosphorylated or mutant aggregation prone recombinant undergoes LLPS, does high molecular weight phospho-tau isolated from human Alzheimer brain....
We studied the effect of microtubule-associated tau protein on trafficking vesicles and organelles in primary cortical neurons, retinal ganglion cells, neuroblastoma cells. Tau inhibits kinesin-dependent transport peroxisomes, neurofilaments, Golgi-derived into neurites. Loss peroxisomes makes cells vulnerable to oxidative stress leads degeneration. In particular, amyloid precursor (APP) axons dendrites, causing its accumulation cell body. APP tagged with yellow fluorescent transfected by...
The neuronal microtubule-associated protein tau plays an important role in establishing cell polarity by stabilizing axonal microtubules that serve as tracks for motor-protein–driven transport processes. To investigate the of intracellular transport, we studied effects expression stably transfected CHO cells and differentiated neuroblastoma N2a cells. Tau causes a change shape, retards growth, dramatically alters distribution various organelles, known to be transported via...
The protein Tau aggregates into tangles in the brain of patients with Alzheimer's disease. In solution, however, is intrinsically disordered, highly soluble, and binds to microtubules. It still unclear what initiates conversion from an innocuous phase high solubility functionality solid-like neurotoxic deposits. Here, we show that microtubule-binding repeats Tau, which are lysine-rich, undergo liquid-liquid separation solution. Liquid-liquid demixing causes molecular crowding...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDomains of tau Protein and Interactions with MicrotubulesN. Gustke, B. Trinczek, J. Biernat, E.-M. Mandelkow, E. MandelkowCite this: Biochemistry 1994, 33, 32, 9511–9522Publication Date (Print):October 16, 1994Publication History Published online1 May 2002Published inissue 16 October 1994https://pubs.acs.org/doi/10.1021/bi00198a017https://doi.org/10.1021/bi00198a017research-articleACS PublicationsRequest reuse permissionsArticle...
Aggregation of amyloid-beta (Abeta) and Tau protein are hallmarks Alzheimer's disease (AD), according to the Abeta-cascade hypothesis, Abeta is considered toxic for neurons a downstream target Abeta. We have investigated differentiated primary hippocampal early localized changes following exposure oligomers. Initial events become evident by missorting endogenous into somatodendritic compartment, in contrast axonal sorting normal neurons. In missorted dendritic regions there depletion spines...
Alzheimer disease is characterized by abnormal protein deposits in the brain, such as extracellular amyloid plaques and intracellular neurofibrillary tangles. The tangles are made of a called tau comprising 441 residues its longest isoform. Tau belongs to class natively unfolded proteins, binds stabilizes microtubules, partially folds into an ordered β-structure during aggregation paired helical filaments (PHFs). Here we show that it possible overcome size limitations have traditionally...
Tau pathology in AD spreads a hierarchical pattern, whereby it first appears the entorhinal cortex, then to hippocampus and later surrounding areas. Based on this sequential appearance, can be classified into six stages ("Braak stages"). The mechanisms agents underlying progression of are matter debate. Emerging evidence indicates that propagation may due transmission protein, but pathways species not well understood. In study we investigated question spreading via small extracellular...
Aggregation and cleavage are two hallmarks of Tau pathology in Alzheimer disease (AD), abnormal fragmentation is thought to contribute the nucleation paired helical filaments. Clearance abnormally modified protein could occur by ubiquitin–proteasome autophagy–lysosomal pathways, major routes for degradation cells. There a debate on which these pathways contributes clearance aggregates formed AD. Here, we demonstrate an inducible neuronal cell model tauopathy that system both into...
We have studied the conformation of tau protein and Alzheimer paired helical filaments (PHF) by several spectroscopic, scattering, imaging methods revealing overall shape polypeptide backbone. Tau behaves in solution as if it were denatured; no evidence for compact folding was detected. The is highly extended, there defined radius gyration, scattering best described that a random (Gaussian) polymer. CD Fourier transform infrared spectroscopy show only minimal content ordered secondary...
Microtubules display the unique property of dynamic instability characterized by phase changes between growth and shrinkage, even in constant environmental conditions. The phases can be synchronized, leading to bulk oscillations microtubules. To study structural basis we have examined growing, shrinking, oscillating microtubules time-resolved cryo-EM. In particular addressed three questions which are currently a matter debate: (a) What is relationship microtubules, tubulin subunits,...
The microtubule-associated protein tau is a natively unfolded in solution, yet it able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer’s disease. In splice isoforms lacking exon 10, this process facilitated by formation β-structure around hexapeptide motif PHF6 (306VQIVYK311) encoded 11. We have investigated structural requirements for PHF polymerization context adult containing four repeats (including 10). addition there exists related PHF6* (275VQIINK280) repeat...
The microtubule‐associated protein tau is the main component of paired helical filaments (PHFs) Alzheimer's disease, most common senile dementia. To understand origin tau's abnormal assembly we have studied influence other cytosolic components. Here report that PHF strongly enhanced by RNA. RNA‐induced PHFs dependent on formation intermolecular disulfide bridges involving Cys 322 in third repeat tau, and it includes dimerization as an early intermediate. Three‐repeat constructs polymerize...
Significance Tau is an important microtubule-associated protein. Although the structure–function relationship of has been intensively studied for many years primarily by molecular biology and biochemical approaches, little still known about mechanisms which interacts with microtubules promotes microtubule assembly. Here, we provide detailed insight into Tau–microtubule association using NMR spectroscopy mass spectrometry. We show that binds to small groups residues, are pathological...
Recent evidence from several laboratories shows that the paired helical filaments of Alzheimer's disease brains consist mainly protein tau in an abnormally phosphorylated form, but mode assembly is not understood. Here we use EM to study constructs derived human brain and expressed Escherichia coli. All or isoforms are rodlike molecules with a high tendency dimerize antiparallel fashion, as shown by antibody labeling chemical crosslinking. The length rods largely determined region internal...
The microtubule-associated protein tau stabilizes microtubules in its physiological role, whereas it forms insoluble aggregates (paired helical filaments) Alzheimer's disease. Soluble is considered a natively unfolded whose residual folding and intramolecular interactions are largely undetermined. In this study, we have applied fluorescence resonance energy transfer (FRET) electron paramagnetic (EPR) to examine the proximity flexibility of domains global folding. FRET pairs spanning molecule...